Two Siblings with Primary Hypothyroidism and Diabetes Secondary to a Novel GLIS3 Variant

Background: Congenital hypothyroidism (CH) is a common endocrine disorder. GLIS3 is a nuclear protein that activates and represses transcription in many tissues beginning in embryogenesis. Additionally, diabetes mellitus may present in varying stages of life as Type 1 Diabetes (autoimmune), Type 2 Diabetes (insulin resistant), or monogenetic. In this case presentation, we present two siblings with hypothyroidism, presumably present from birth, and diabetes secondary to a novel GLIS3 variant. Case Presentation: An 8-year-old male born to consanguineous parents presented for care after immigrating to the United States. Key findings included developmental delay since birth, short stature, and calf hypertrophy. A brain MRI, thyroid ultrasound, and a cytogenic SNP microarray found goiter and nondiagnostic runs of homozygosity on chromosomes 9 and 13. Thyroid function tests (TFT) revealed an elevated TSH (143.41 mIU/L, reference range: 0.5-4.30 mIU/L) and very low free T4 (0.2 ng/dL, reference range: 0.9-1.4 ng/dL). Initiation of levothyroxine improved height and calf hypertrophy. Subsequently, he presented with polyuria, polydipsia, weight loss, hyperglycemia (170 mg/dL, reference range: 70-100 mg/dL), and an elevated HbA1c (12.8%, reference range: 4.2-6.3%) consistent with diabetes mellitus. Low doses of insulin maintained control of symptoms. Maturity onset diabetes in youth (MODY) genetic testing and diabetes-related antibodies were negative. Subsequently, his 2-week-old female sibling presented with low birth weight, hyperglycemia (251 mg/dL, reference range: 50-96 mg/dL), extremely elevated TSH (>500 mIU/L, reference range: 0.8-8.20 mIU/L), and low free T4 (0.23 ng/dL, reference range: 0.9-1.4 ng/dL) consistent with neonatal diabetes (NDM) and CH. Levothyroxine and diluted insulin were initiated. Comprehensive neonatal diabetes gene analysis confirmed a pathologic GLIS3 variant (c.728dup). This prompted reflex GLIS3 testing in the older sibling, revealing the same GLIS3 variant. Abdominal and renal ultrasounds revealed kidney abnormalities in both siblings. TFT remained normal with levothyroxine in both siblings. The older brother has continued to require insulin at very low doses for his body weight. The younger sister required diluted insulin until she was 8-months-of age, at which time she remained euglycemic without requiring insulin. Conclusions: GLIS3 encodes for a transcription factor located at 9p24. Variants of GLIS3 that affect temporal and/or tissue-specific gene expression may result in a variety of clinical phenotypes, which include CH, NDM, intrauterine growth retardation, developmental delay, renal disease, and others. CH and NDM have been reported in 21 previous cases of GLIS3 variants. We add two new cases to the literature, describe how their diagnosis was reached, the varying phenotypic expressions, and responses to therapy. Continued research is needed to identify the spectrum of phenotypes associated with GLIS3 variants and further understand its association with diabetes and hypothyroidism.